Bipolar disorder (BD) is a serious psychiatric illness involving recurrent episodes of depression and mood elevation that affects up to 4% of the population.1 Over the past decade, important new treatment options have arisen, including 6 second-generation antipsychotics (SGAs). Second-generation antipsychotics compared to first-generation antipsychotics have fewer neurological (acute extrapyramidal symptoms and tardive dyskinesia) adverse effects, but their use may be limited by weight gain and metabolic problems, sedation, or akathisia.2
Obesity is an important public health problem that may be associated with SGA treatment and is particularly evident in patients with BD.3 Previous studies suggest obese compared to nonobese patients with BD may have greater baseline illness severity and poorer affective outcomes,4–6 highlighting the need for further studies to develop effective treatment strategies for obese patients with BD.
Ziprasidone is an SGA that demonstrated acute and preventive antimanic effects in controlled efficacy studies.2,7 Thus, ziprasidone was significantly more efficacious than placebo as monotherapy for acute mania8,9 and as adjunctive therapy (added to lithium or valproate) for maintenance treatment of bipolar I disorder.10 Although efficacy studies have informed treatment with ziprasidone of patients with BD with less complex illness, there remain a limited number of effectiveness studies to adequately inform the use of ziprasidone when treating more complicated patients encountered in clinical practice.11,12 Furthermore, despite potential metabolic advantages of ziprasidone compared to other SGAs,13 physicians fail to prescribe this medicine preferentially in patients with known metabolic risk factors,14 possibly owing to a lack of data regarding the efficacy and tolerability of ziprasidone in such patients. We used an open-label, uncontrolled, observational design and a sample of outpatients with BD primarily already receiving combination pharmacotherapy, to assess ziprasidone effectiveness in obese compared to nonobese patients with BD.
MATERIALS AND METHODS
Outpatients with BD treated at the Stanford University Bipolar Disorders Clinic were assessed with the Systematic Treatment Enhancement for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form,15,16 as they received treatment guided by model practice procedures.15,17 This research was approved by the Stanford University Administrative Panel on Human Subjects, and patients provided verbal and written informed consent before participation. We assessed patients in whom open-label ziprasidone was naturalistically combined with other pharmacotherapies (including in only one case no other pharmacotherapy) between April 27, 2001, and February 28, 2010.
The primary effectiveness measures were rates of ziprasidone discontinuation and of addition of subsequent psychotropic medications. Other effectiveness parameters assessed at baseline (immediately before ziprasidone for trials started at Stanford, or at first visit taking ziprasidone in trials started before Stanford) and at last visit taking ziprasidone included: (1) clinical status (percentage of patients with euthymia vs syndromal or subsyndromal depression vs syndromal or subsyndromal mood elevation); (2) Clinical Global Impression-Severity of Illness (CGI-S) scores; (3) Global Assessment of Functioning (GAF) scores; and (4) weight. Clinical status for syndromal depression and mood elevation was based on criteria in the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR).18 Subsyndromal depression and mood elevation were defined as having more than 2 threshold DSM-IV-TR symptoms of either polarity, but not meeting DSM-IV-TR criteria for a syndromal mood episode, whereas euthymia comprised having no more than 2 threshold DSM-IV-TR symptoms of either polarity.16 Obese and nonobese patients were defined as those having a body mass index (BMI) 30 kg/m2 or greater, or less than 30 kg/m2, respectively, at first visit.
Descriptive statistics were compiled. Continuous measures were compared with paired and unpaired t tests and for nonnormally distributed parameters with corresponding nonparametric tests (Wilcoxon sign rank and Mann-Whitney U tests), as indicated. Categorical parameters were compared with the χ2 and Fisher exact tests, as indicated. Relationships between continuous parameters were assessed with parametric (Pearson) and nonparametric (Spearman rank) correlations, as indicated. A significance threshold of P < 0.05 was used, with no correction for multiple comparisons.
Sample Description and Baseline Characteristics
Eighty-two outpatients with BD had ziprasidone trials. Ziprasidone was started at Stanford in 71 patients and before Stanford in 11 patients, with these groups being statistically similar for all demographic and illness characteristic parameters (Table 1) and having only a few minor statistically significant clinical outcome differences, so that data for these groups were generally pooled throughout this report. Similarly, 14 patients were participants in a ziprasidone weight loss study19 but were generally similar to the 68 nonparticipants with respect to demographics, baseline characteristics, and clinical outcomes, so that data for these groups were pooled throughout this report. In contrast, 40 obese patients compared to 42 nonobese patients were significantly older (45.0 vs 37.4 years, t = −2.9, df = 80, P = 0.004), had greater illness duration (25.7 vs 16.7 years, t = −3.3, df = 80, P = 0.001; indicated by asterisks in Table 1), and had numerous substantive statistically significant differences with respect to clinical outcomes, as described in the following text.
In both the obese patients and the nonobese patients, baseline clinical status was most often syndromal or subsyndromal depressive symptoms (50.0% vs 57.1%, χ2 = 0.4, df = 1, P = 0.66) or euthymia (37.5% vs 26.2%, χ2 = 1.2, df = 1, P = 0.34). The obese compared to the nonobese patients were more likely to have started ziprasidone for weight control (58.3% vs 25.7%) as opposed to for mood symptoms (41.7% vs 74.3%, χ2 = 7.7, df = 1, P = 0.008).
Concurrent Medications and Ziprasidone Dosing
Because the obese patients compared to the nonobese patients had similar concurrent medication numbers and patterns, pooled data are presented. At baseline, the patients were taking mean ± SD (median) of 3.6 ± 1.7 (4) prescription psychotropic medications (other than ziprasidone) and 1.2 ± 1.4 (1) prescription nonpsychotropic medications. Of the trials, 98.8% were combination therapy (ziprasidone plus one or more concurrent prescription psychotropics), with 74.4% involving ziprasidone plus 3 or more prescription psychotropics. Of the patients, 86.6% were taking mood stabilizers (lamotrigine, 54.9%; 301.9 ± 127.1  mg/d; lithium, 35.4%; 928.5 ± 377.9  mg/d; valproate, 11.0%; 1250.0 ± 707.1  mg/d; and 1.2% [1 patient] taking carbamazepine, 600 mg/d). Of the patients, 68.3% were taking at least one SGA (quetiapine, 36.6%; aripiprazole, 19.5%; olanzapine, 15.9%; and risperidone, 9.8%); 51.2% were taking antidepressants, 39.0% were taking hypnotics/benzodiazepines, and 25.6% were taking anticonvulsants other than lamotrigine, valproate, or carbamazepine.
Because the obese compared to the nonobese patients had similar ziprasidone dosing patterns, pooled data are presented. Ziprasidone was generally administered in a single daily dose, most often given with dinner and/or a snack at bedtime, with an overall final dose of 134.3 ± 79.0 (150) mg/d, after 489 ± 590 (199.5) days of taking ziprasidone at Stanford. In the 71 trials started at Stanford, ziprasidone was initiated at 68.2 ± 25.0 (80) mg/d, increased to at least 160 mg/d in 78.9% (56/71) of the patients after 19 ± 39 (6) days, with maximum dose of 181.8 ± 76.8 (160) mg/d after 79 ± 268 (17) days.
Ziprasidone Discontinuation Rates and Reasons
The obese compared to the nonobese patients had a lower ziprasidone discontinuation rate (42.5% [17/40] vs 71.4% [30/42]; χ2 = 7.0; df = 1; Fisher exact test, P = 0.01; Fig. 1, left side), and a significantly longer mean ± SD (median) duration of ziprasidone treatment (641 ± 682 [355.5] days vs 344 ± 450 [127.5] days, respectively; U = 609.0, Z = −2.1, P = 0.03) but a statistically similar time to discontinuation among those who discontinued (85 ± 70  vs 205 ± 260 [92.5] days). For all 82 patients, there was no statistically significant correlation between time to ziprasidone discontinuation and demographic/illness characteristics, baseline, final, and change in weight, BMI, CGI-S, and GAF; number of concurrent prescription psychotropic medications; baseline, maximum, and final ziprasidone dose; and time to maximum ziprasidone dose.
The patients who discontinued compared to those who continued ziprasidone were less educated, more often had a history of alcohol abuse, and less often had a history of psychiatric hospitalization (but were statistically similar with respect to other characteristics [Table 1]), and had lower final ziprasidone doses (110.0 ± 60.7  vs 166.9 ± 89.3  mg/d, respectively; t = 3.4, df = 80, P = 0.001). However, the obese compared to the nonobese patients were statistically similar with respect to final dose and all demographic and illness characteristics (aside from age and illness duration) in Table 1.
Because the obese compared to the nonobese patients had a similar pattern of reasons for discontinuation, pooled data are presented. Ziprasidone was most commonly discontinued owing to adverse effects (in 26.8%) and inefficacy for mood (in 23.2%). Adverse effect discontinuations were most often due to central nervous system (CNS) adverse effects (in 22.0%), including sedation in 8.5%. Discontinuations due to inefficacy for mood were most often due to inefficacy for depression (in 13.4%), whereas 9.8% discontinued owing to inefficacy for mania/hypomania/mixed mood/rapid cycling. Additionally, discontinuations occurred in 4.9% of the patients owing to inefficacy for weight loss after 103 ± 14 (100.5) days, in 1.2% of the patients owing to cost after 131 days, and in 1.2% owing to other reasons after 1074 days.
Subsequent Additional Pharmacotherapy Rates and Reasons
The obese compared to the nonobese patients had a higher rate of addition of subsequent psychotropic medication (62.5% vs 35.7%, respectively; χ2 = 5.9; df = 1; Fisher exact, P = 0.03; Fig. 1, right side) but a statistically similar time to addition of another psychotropic (150 ± 155  vs 143 ± 192  days, respectively; U = 187.0, Z = −0.01, P = 1.0).
Because the obese compared to the nonobese patients had a similar pattern of reasons for subsequent additional pharmacotherapy, pooled data are presented. Subsequent additional pharmacotherapy was administered in 22.0% of trials for depressive symptoms, in 18.3% for anxiety/insomnia, in 2.4% for manic/hypomanic/mixed symptoms, in 2.4% for weight control, and in 3.7% for other reasons.
Mood, Functioning, and Weight Control Benefits
The obese compared to the nonobese patients had a higher rate of shift from baseline visit noneuthymic mood to final-visit euthymic mood (27.5% [11/40] vs 0.0% [0/42]; χ2 = 13.3; df = 1; Fisher exact test, P = 0.0002). The obese (but not the nonobese) patients also had statistically significant though clinically modest CGI-S improvement (baseline, 3.8 ± 1.2; final, 3.2 ± 1.4; change, −0.6 ± 1.6; t = 2.2; df = 39; P = 0.03) and GAF improvement (baseline, 60.3 ± 7.2; final, 63.5 ± 9.3; change, +3.3 ± 8.0; t = −2.6; df = 39; P = 0.01).
In the obese compared to the nonobese patients, ziprasidone yielded more weight loss (−20.7 ± 33.0 [−14.5] vs −0.6 ± 22.2  lbs; U = 476.5; z = −3.4; P = 0.001; Fig. 2, left side) and a higher rate of clinically significant (≥7%) weight loss (45.0% vs 19.0%; χ2 = 6.4; df = 1; Fisher exact test, P = 0.02; Fig. 2, right side). Overall, weight change correlated significantly with GAF change (Spearman rho = −0.2, n = 82, P = 0.047) but not with CGI-S change.
Because the obese compared to the nonobese patients had a similar pattern of adverse effects, pooled data are presented. Ziprasidone yielded discontinuations for adverse effects (primarily CNS adverse effects) in 26.8% but was otherwise generally well tolerated. Overall, mean ratings for CNS (tremor, sedation, headache, memory problems, akathisia, and other extrapyramidal symptoms) and gastrointestinal (nausea, vomiting, diarrhea, and constipation) adverse effects, dry mouth, sexual dysfunction, and increased appetite were all low at baseline and did not change significantly at the last visit.
We found that the obese compared to the nonobese patients with bipolar disorder had more mood and functioning benefits and weight loss and less discontinuation and longer treatment duration with ziprasidone, suggesting that among those already taking combination pharmacotherapy, the obese compared to the nonobese patients may be better candidates for adding ziprasidone.
In this effectiveness study, we paid attention to not only mood and functioning benefits and adverse effects but also somatic (weight control) benefits. Enhanced efficacy for mood and functioning and weight control (rather than demographic and illness characteristics and final dose) may have contributed importantly to the lower ziprasidone discontinuation rate in the obese compared to the nonobese patients. Specifically, ziprasidone yielded in the obese compared to the nonobese patients a higher rate of shift to final-visit euthymia and more weight loss and in the obese but not in the nonobese patients significant improvements in CGI and GAF, perhaps increasing the likelihood of continuing ziprasidone in the obese patients. Our unexpected finding of the obese compared to the nonobese patients having better outcomes for mood may have been in part related to more often starting ziprasidone for weight loss and achieving weight loss in the former compared to the latter group. Such weight loss could be either a cause or effect of mood improvement. Our correlational analyses suggested that the degree of weight change was associated with some but not all mood and functioning benefits.
The relatively favorable outcome in the obese compared to the nonobese patients in our study contrasts with prior reports of poorer mood outcomes in obese compared to nonobese patients with BD.4–6 This could be related to our obese compared to nonobese patients having more similar baseline bipolar illness severity, with the sole exception of longer illness duration in obese patients. In contrast, 2 studies reporting poorer mood outcome in obese patients with BD noted more evidence of greater baseline bipolar illness severity in obese compared to nonobese patients, including longer illness duration and chronic illness course4 as well as greater number of past mood episodes, longer duration of acute episode, and higher mean baseline Hamilton Depression Rating Scale score.5 In a third study, overall medical burden correlated with baseline depression severity in patients with BD, although comorbid substance use disorders were associated with lower BMI.6
Despite the greater benefits we observed in the obese compared to the nonobese patients with BD, pooling both groups, we found a substantial overall ziprasidone discontinuation rate of 57.8%, which may have been related to the degree of pharmacotherapy complexity in this cohort. Indeed, 74.4% of our patients were taking ziprasidone plus 3 or more prescription psychotropics. Greater complexity of pharmacotherapy has been associated with higher levels of depressive illness burden and suicidality20 and thus may reflect more challenging and treatment-refractory bipolar illness course. Although polypharmacotherapy is highly prevalent in the management of BD, with as many as 1 in 5 patients with BD taking at least 4 medications20 and may be necessary to maintain long-term stability,21 there is a lack of systematic assessment of ziprasidone effectiveness when administered in such regimens. Our data indicated that among the patients taking complex pharmacotherapy, although most obese patients obtained sufficient benefit to continue ziprasidone, approximately 70% of the nonobese patients discontinued ziprasidone.
The current US ziprasidone prescribing information recommends doses of 80 to 160 mg/d for acute bipolar manic/mixed episodes and for longer-term treatment recommends continuing the dosage necessary to maintain symptom remission. In our study, there were no significant differences in dosing patterns between the obese and the nonobese patients. Pooling these groups, the mean final dose of 134.3 mg/d was somewhat higher than 120 mg/d, which compared to 80 or 160 mg/day, yielded superior relapse prevention in post hoc analysis of the ziprasidone adjunctive bipolar maintenance registration study.10,22 Furthermore, our finding that patients who discontinued compared to those who continued had lower final ziprasidone doses (median, 120 vs 160 mg/d, respectively) contrasts with the results of a post hoc analysis of the randomized controlled adjunctive maintenance study, which found less ziprasidone discontinuation in patients taking 120 mg/d compared to 80 or 160 mg/d.22 Additional effectiveness trials are needed to determine whether or not optimal ziprasidone dosing in longer-term BD treatment involves using the higher end of the 80- to 160-mg/d range.
This study has noteworthy limitations, including small sample size and use of an open-label, uncontrolled, observational design. The degree of complexity of pharmacotherapy in the current study limits the generalizability of our findings to patients receiving less complex medication regimens. Our tertiary teaching hospital clinic sample (86.6% whites, relatively affluent, highly educated, privately insured, and with low prevalence of alcohol/substance use disorder) lacked several characteristics commonly associated with poor treatment response and may have further limited generalizability. Owing to the substantial adherence limitations of taking medication twice daily with food and the risk of sedation with higher doses, we most often administered ziprasidone once daily (at dinner or at bedtime with food). This approach, which entailed less frequent dosing than the twice-daily-with-food prescribing information recommendation seemed to be generally well tolerated but could have influenced therapeutic efficacy. In addition, prior or subsequent additional medication or nonmedication interventions may have contributed to the observed outcomes.
Nevertheless, our observations support the contention that more research is indicated. Specifically, controlled and additional observational studies seem warranted to confirm these preliminary findings, suggesting that ziprasidone may be more effective in obese compared to nonobese patients with BD already receiving combination pharmacotherapy.
AUTHOR DISCLOSURE INFORMATION
Conflicts of interest and sources of funding (past 36 months): Shefali Miller received honoraria from Pamlab Inc. Natalie Rasgon has received grant/research support from Bayer Pharmaceuticals, American Diabetes Association, Abbott Laboratories, GlaxoSmithKline, Pfizer, Inc, and Wyeth Pharmaceuticals; has served as a consultant to Takeda Pharmaceuticals and Wyeth Pharmaceuticals, and received lecture honoraria from Bristol-Myers Squibb, Forest Laboratories, and Pfizer, Inc. Terence Ketter has received grant/research support from Agency for Healthcare Research and Quality, AstraZeneca Pharmaceuticals, Cephalon Inc, National Institute of Mental Health, Eli Lilly and Company, Pfizer Inc, and Sunovion; served as consultant to Merck and Company; served as a board member of Astellas Pharmaceuticals, Bristol-Myers Squibb, Cephalon Inc, GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Merck & Co, Sunovion, and Avanir Pharmaceuticals; received lecture honoraria from AstraZeneca, Abbott Laboratories, GlaxoSmithKline, and Pfizer, Inc; received royalties from American Psychiatric Publishing, Inc; is related to an employee of Janssen Pharmaceutica Products (Nzeera Ketter, MD, spouse); and holds stock in Johnson & Johnson (Nzeera Ketter, MD, spouse). Po Wang has received grant/research support from Agency for Healthcare Research and Quality, AstraZeneca Pharmaceuticals, Cephalon Inc, National Institute of Mental Health, Eli Lilly and Company, Pfizer Inc, and Sunovion; served as consultant to Synosia; and received lecture honoraria from AstraZeneca, GlaxoSmithKline, and Bristol-Myers Squibb. For the remaining authors, none were declared.
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